Norovirus (NV) is the leading cause of diarrhea in patients of all ages worldwide. After rotavirus, NV is the 2nd most frequent cause of pediatric gastroenteritis and hospitalizations for diarrhea, and is estimated to cause 200,000 annual deaths. When rotavirus vaccination is broadly implemented, NV is likely to become the leading cause of pediatric diarrheal hospitalization and deaths. However, the true burden of NV in young children and the extent of acquired immunity remain incompletely understood. Human NV infections are divided into two predominant genogroups (GI and GII), and at least 36 genotypes. Susceptibility to NV infection is thought to be mediated by viral binding to histo-blood group antigens, whose specificity as receptors varies by NV genotype. GII type 4 (GII.4) predominates in outbreaks and sporadic infections for which data are available. An evolving series of GII.4 variants has been detected over the past decade, due to mutations in the major NV capsid protein that change the configuration of the binding site and enable evasion of herd immunity in an epidemiological pattern reminiscent of influenza. Major questions raised by the genetics of NV include the extent and duration of cross-reacting, genotype- and GII.4 variant-specific immunity, and the implications for vaccine design and testing. We propose to conduct a newborn cohort study in a peri-urban community of Lima, Peru, where we have worked since the 1980s, to address these questions in a setting of frequent natural NV infection. Our collaboration with Emory University provides access to a leading NV laboratory with the expertise and state-of-the-art reagents to evaluate naturally-acquired immunity. We begin with newborns because first infections occur very early in life. Our preliminary data demonstrate much higher genetic heterogeneity than is assumed to be the norm: 18 different genotypes were identified of which 40% were GII.4, including 5 different variants. Repeat infections with the same genotype or GII.4 variant were rare, suggesting acquired genotype-specific immunity. We proposed to extend our knowledge of NV epidemiology in endemic diarrhea in young children with this proposal to address issues key to effective vaccine design and deployment. We will quantify the role of NV genotypes in mild and moderate gastroenteritis and evaluate acquisition of protective immunity by correlating serum, saliva and stool antibodies to NVs with NV disease, infection, length of shedding and linear growth. In addition, we will evaluate the role of sapoviru as an enteric pathogen, and will explore the use of community sewage surveillance to track circulating viral strains.